tbuckley/cabot-search huggingface dataset:
S267: PROPERDIN-BLOCKING ANTIBODIES ATTENUATE COMPLEMENT ALTERNATIVE PATHWAY ACTIVATION TRIGGERED BY CELL-FREE HEME IN SICKLE CELL DISEASE MODELS
Authors: T. Trovati Maciel, R. Cofiell, C. Carvalho, S. Allali, R. Rignault, A. Bennet, Y. Dai, P. Tamburini, C. Gasteyger, O. Hermine, S. K. Kim
Journal: HemaSphere (2022)

Background: Complement activation may play an important role in sickle cell disease (SCD) pathophysiology. Heme has been identified as a trigger of complement activation in SCD patients and is present in excess during severe vaso-occlusive crises. Heme is also a DAMP (damage associated molecular pattern) and induces thrombo-inflammation through tissue factor expression. ALXN1820 is a bi-specific VHH nanobody that simultaneously binds human albumin and properdin, thereby effectively and selectively inhibiting alternative pathway (AP) activation and formation of C3 and C5 convertases. The safety of ALXN1820 has been assessed in non-human primates and is currently being tested in a phase 1 study in healthy participants. Aims: 1) To assess if complement activation and heme are functionally linked; 2) To investigate the therapeutic potential of ALXN1820 in in vitro SCD models and in in vivo SCD models using a mouse properdin-blocking monoclonal antibody (mAb), 14E1. Methods:In vitro, complement inactivated C3b (iC3b) and C5b-9 deposition on red blood cells (RBCs) from patients with SCD and complement iC3b and C5b-9 deposition on the endothelial cell line HMEC-1 were assessed by flow cytometry after exposure to heme +/- ALXN1820. In vivo, in Townes SCD mice, vaso-occlusion and hyper-hemolysis were induced by intravenous heme injection (50 µmol/kg) or hypoxia-reoxygenation (8% O2 for 3h then 21% O2 for 1h) in the presence and absence of 14E1 (40 mg/kg), a mouse-specific properdin inhibitor. Vaso-occlusion was measured by staining RBCs with immunofluorescence-labeled Ter-119 antibodies on lung and liver sections. C3b and C5b-9 deposition on SCD RBCs was assessed by flow cytometry. Markers of hemolysis (bilirubin, lactate dehydrogenase, free hemoglobin, free heme) were quantified in plasma using commercial assays. Results: In RBCs from patients with SCD, cell-free heme triggered marked iC3b and C5b-9 deposition (Table). Deposition was blocked in the presence of ALXN1820 by >95% for iC3b and by >85% for C5b-9. HMEC-1 cells exposed to heme showed marked deposition of iC3b and C5b-9. In the presence of ALXN1820, deposition was blocked by >70% for iC3b and >85% for C5b-9. Pretreatment of mice with 14E1 markedly ameliorated vaso-occlusion and reduced both C3b and C5b-9 deposition on RBCs, and hemolysis biomarkers. Image:Summary/Conclusion: These data strengthen the hypothesis that in SCD, cell-free heme is a potent trigger of complement AP activation, which can be blocked by targeting properdin. Investigating the efficacy and safety of anti-properdin ALXN1820 in patients with SCD is warranted as a novel approach to treatment of acute and chronic SCD complications.
Giant cell myocarditis after first dose of BNT162b2 – a case report
Authors: Valentin G. Hirsch, Sven Schallhorn, Carolin Zwadlo, Johanna Diekmann, Florian Länger, Danny David Jonigk, Tibor Kempf, Heinz‐Peter Schultheiss, Johann Bauersachs
Journal: European Journal of Heart Failure (2022)
Association of a Dominant T-Cell Clone in Peripheral Blood With Time to Systemic Treatment in Patients With Stage IB Mycosis Fungoides
Authors: Suravi Raychaudhuri, Yann Charli-Joseph, Chiung-Yu Huang, Michelle A. Mintz, Laura B. Pincus, Weiyun Z. Ai
Journal: JAMA Dermatology (2022)

This cohort study of data from 39 patients assesses whether the presence of a dominant T-cell receptor clone in peripheral blood is associated with time to systemic treatment in patients with stage IB mycosis fungoides.
P1119: THE ORAL PI3KΔ INHIBITOR LINPERLISIB FOR THE TREATMENT OF RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA: A SINGLE-ARM MULTICENTER PHASE 2 CLINICAL TRIAL
Authors: T. wang, X. sun, L. qiu, H. su, J. cao, Z. li, Y. song, L. zhang, S. yi, L. qiu, J. zhou, H. wu, W. zhang, J. li, K. zhou, H. zhou, Y. yang, Z. li, H. cen, Z. cai, Z. zhang, W. fu, J. jin, F. li, W. wu, X. gu, W. zhu, L. liu, Z. li
Journal: HemaSphere (2022)

Background: The orally active phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor linperlisib which conveyed acceptable safety and notable efficacy for B-cell lymphoma medications in a previous phase 1 dose escalation study was investigated in this phase 2 study for the treatment of relapsed and/or refractory follicular lymphoma (FL) patients who had received at least two prior systemic treatments Aims: To explore the satefy and efficacy of linperlisib in FL Methods: Linperlisib was administered at 80 mg qd, po in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome was the objective response rate (ORR), while secondary outcomes included the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and the drug safety profile. Results: For 84 FL patients in the full analysis set (FAS) the ORR was 79.8% (95% CI: 69.6-87.8, 67 patients), with 13 patients achieving a complete response and 54 a partial response. The median DOR was 12.3 months (range, 9.3-15.9) with 6-month and 12-month DORs of 80.0% (95% CI: 67.4-88.1) and 55.3% (95% CI: 40.6-67.8). The median PFS was 13.4 months (95% CI: 11.1-16.7), with 6-month and 12-month PFS rates of 78.7% (95% CI: 67.5-86.3) and 53.1% (95% CI: 40.3-64.3). The median OS was not reached, while 6-month and 12-month OS rates were 97.6% (95% CI: 90.6-99.4) and 91.4% (95% CI: 82.7-95.8), respectively. The most frequent any-grade treatment related AEs (TRAE) were neutropenia (47%), hypertriglyceridemia (25%), while the most frequent TRAEs ≥ grade 3 were neutropenia (15%), infectious pneumonia (19.4%) and interstitial lung disease (6.5%). AEs that were potentially immune-mediated, such as diarrhea, colitis, pneumonitis, and transaminitis, were observed at significantly lower incidences of occurrence. Summary/Conclusion: Linperlisib demonstrated compelling clinical efficacy and a promising safety profile, which has the potential to surpass the approved PI3K inhibitors for the treatment of relapsed or refractory FL patients after two prior therapies.
Single-cell transcriptomics and surface epitope detection in human brain epileptic lesions identifies pro-inflammatory signaling
Authors: Pavanish Kumar, Amanda Lim, Sharifah Nur Hazirah, Camillus Jian Hui Chua, Adeline Ngoh, Su Li Poh, Tong Hong Yeo, Jocelyn Lim, Simon Ling, Nursyuhadah Binte Sutamam, Enrico Petretto, David Chyi Yeu Low, Li Zeng, Eng-King Tan, Thaschawee Arkachaisri, Joo Guan Yeo, Florent Ginhoux, Derrick Chan, Salvatore Albani
Journal: Nature Neuroscience (2022)

Abstract Epileptogenic triggers are multifactorial and not well understood. Here we aimed to address the hypothesis that inappropriate pro-inflammatory mechanisms contribute to the pathogenesis of refractory epilepsy (non-responsiveness to antiepileptic drugs) in human patients. We used single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to reveal the immunotranscriptome of surgically resected epileptic lesion tissues. Our approach uncovered a pro-inflammatory microenvironment, including extensive activation of microglia and infiltration of other pro-inflammatory immune cells. These findings were supported by ligand–receptor (LR) interactome analysis, which demonstrated potential mechanisms of infiltration and evidence of direct physical interactions between microglia and T cells. Together, these data provide insight into the immune microenvironment in epileptic tissue, which may aid the development of new therapeutics.
Food allergy, mechanisms, diagnosis and treatment: Innovation through a multi‐targeted approach
Authors: Sayantani B. Sindher, Andrew Long, Andrew R. Chin, Angela Hy, Vanitha Sampath, Kari C. Nadeau, R. Sharon Chinthrajah
Journal: Allergy (2022)

The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, large-scale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.
Correction: Rate of pancreatic cancer following a negative endoscopic ultrasound and associated factors
Authors: Dominic King, Umair Kamran, Amandeep Dosanjh, Ben Coupland, Jemma Mytton, John S. Leeds, Manu Nayar, Prashant Patel, Kofi W. Oppong, Nigel J. Trudgill
Journal: Endoscopy (2022)

Correction to: Rate of pancreatic cancer following a negative endoscopic ultrasound and associated factorsEndoscopy eFirstDOI: 10.1055/a-1784-1661
P1314: PURIFICATION AND FUNCTIONAL CHARACTERIZATION OF CD34+ CELLS FROM CRYOPRESERVED APHERESIS PRODUCTS OF PATIENTS WITH BONE MARROW INFILTRATING MALIGNANCIES
Authors: F. Muller, K. Wendland, S. Petkovic, J. Strobel, A. Mackensen
Journal: HemaSphere (2022)

Background: In vivo models to study activation of human T cells or NK cells against malignancies depend on immune compromised mice in which a xeno-transplanted tumor is treated with allogeneic T cells not matching the HLA of the tumor. Immunologically, these models are far from representative. With the goal of developing a lymphoma-matching, humanized model system, we tested the potency of cryo-preserved, human CD34+ hematopoietic stem cells to engraft the murine bone marrow niche of immune compromised mice, which are known to take human tumor grafts at high rates, thus, allowing for autologous primary tumor grafts following BM engraftment. Aims: To develop and characterize a lymphoma-matching, humanized mouse model with funtinal immune cell subsets. Methods: We developed a method to isolate viable human CD34hi and CD34int cells from cryopreserved apheresis products of patients with BM infiltrating disease such as multiple myeloma and B-cell NHL. Colony-forming potential was assessed using CFU assays. Engraftment potential was tested by injecting irradiated NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice with CD34hi or CD34int populations and engraftment quality and duration was assessed by flow cytometry of murine peripheral blood and of spleen and BM post mortem. Results: Initial frequency of CD34+ cells in cryopreserved apheresis products ranged from 1-5% and was enriched to > 96% CD34hi cells after CD34 MACS separation. A large population of CD34int cells not selected by CD34 MACS was purified by column-free CD3 T cell depletion. While CD34hi cells gave rise to all lineages in in vitro CFU assays, CD34int cells produced fewer colonies overall, with a less efficient differentiation towards myeloid lineage compared to CD34hi. In vivo engraftment of CD34hi cells from 3 of 3 patients gave rise to human CD45+ immune cells. In contrast, none of CD34int cells resulted in more than 20% human cells in peripheral blood. Engraftment of immune cell subsets varied between the three distinct donors. Generally, neutrophils and monocytes were detected from week 3 to 4 and rates declined quickly to undetectable at week 9, B cell engraftment showed highest variability between donors.T-cell engraftment followed from week 4 to 6. From 9 weeks, human T-cells further expanded without signs of GvHD. Functional T cell analysis showed enrichment of effector memory T cells and low numbers of naïve T cells which frequently showed exhausted or senescent phenotype. Summary/Conclusion: Cryopreserved apheresis products present a possible source of CD34+ stem cells that can be further differentiated into CD34hi and CD34int cells with distinct stemness features and engraftment potential. Long-term engraftment of T-cells from cryopreserved, disease-bearing BM from patients is feasible and may allow e.g. testing of T-cell recruiting agents such as bispecific antibodies or CAR T cells.
Use of Dental Defects Associated with Low-Dose di(2-Ethylhexyl)Phthalate as an Early Marker of Exposure to Environmental Toxicants
Authors: Ai Thu Bui, Sophia Houari, Sophia Loiodice, Dominique Bazin, Jérémy Sadoine, Nicolas Roubier, Elsa Vennat, Thu Thuy Tran, Ariane Berdal, Jean-Marc Ricort, Sakina Mhaouty-Kodja, Sylvie Babajko
Journal: Environmental Health Perspectives (2022)

Background: Markers of exposure to environmental toxicants are urgently needed. Tooth enamel, with its unique properties, is able to record certain environmental conditions during its formation. Enamel formation and quality are dependent on hormonal regulation and environmental conditions, including exposure to endocrine disrupting chemicals (EDCs). Among EDCs, phthalates such as di-(2-ethylhexyl) phthalate (DEHP) raise concerns about their contribution to various pathologies, including those of mineralized tissues. Objectives: The effects of exposure to low-doses of DEHP on the continually growing incisors were analyzed in mouse males and females. Methods: Adult male and female C57BL/6J mice were exposed daily to 0.5, 5, and 50μg/kg per day DEHP for 12 wk and their incisors clinically examined. Incisors of males were further analyzed by scanning electron microscopy (SEM), micro X-ray computed tomography (micro-computed tomography; μCT), and nanoindentation for the enamel, histology and real-time quantitative polymerase chain reaction (RT-qPCR) for the dental epithelium. Results: Clinical macroscopic observations of incisors showed various dose-dependent dental lesions such as opacities, scratches, and enamel breakdown in 30.5% of males (10 of 34 total incisors across three independent experiments), and 15.6% of females (7 of 46 incisors) at the highest dose, among which 18.1% (6 of 34 total incisors across three independent experiments) and 8.9% (4 of 46 incisors), respectively, had broken incisors. SEM showed an altered enamel surface and ultrastructure in DEHP-exposed male mice. Further characterization of the enamel defects in males by μCT showed a lower mineral density than controls, and nanoindentation showed a lower enamel hardness during all stages of enamel mineralization, with more pronounced alterations in the external part of the enamel. A delay in enamel mineralization was shown by several approaches (μCT, histology, and RT-qPCR). Discussion: We conclude that DEHP disrupted enamel development in mice by directly acting on dental cells with higher prevalence and severity in males than in females. The time window of DEHP effects on mouse tooth development led to typical alterations of structural, biochemical, and mechanical properties of enamel comparable to other EDCs, such as bisphenol A. The future characterization of dental defects in humans and animals due to environmental toxicants might be helpful in proposing them as early markers of exposure to such molecules. https://doi.org/10.1289/EHP10208
S133: OFF-THE-SHELF CD33 CAR-NK CELL THERAPY FOR RELAPSE/REFRACTORY AML: FIRST-IN-HUMAN, PHASE I TRIAL
Authors: R. Huang, Q. Wen, X. Wang, H. Yan, Y. Ma, M. Wang, X. Han, L. Gao, L. Gao, C. Zhang, X. Zhang
Journal: HemaSphere (2022)

Background: The primary results of CAR-T therapy for patients with R/R AML has shown limited efficacy and severe side-effect. One of the main challenges is that current targets for myeloid malignancies are either widely expressed on healthy hemopoietic stem cells such as CD33 or specific for a group of tumor cells presented as Lewis Y antigen, which could cause lasting bone marrow depression induced by “on target off tumor” side-effect or target negative relapse. Therefore, to receive a balance, we designed a CD33 CAR to recognize AML cells and using NK cells to replace T cells as the carrier to eliminate tumor cells. The CD33 CAR NK cells have combined the wide-expression advantage of CD33 target and the safety of NK cells. Aims: To evaluate the safety and primary efficacy of CD33 CAR NK cells Methods: 5 qualified subjects with R/R AML aged between 18 and 65 years-old were enrolled and received round(s) of infusion of anti-CD33 CAR NK cells (6×108, 1.2×109 or 1.8×109 cells per round after the precondition with Fludarabine (30mg/m2) and Cytoxan 300-500mg/m2 for 3 days to 5 days, determined by tumor burden at baseline. We investigated the response rate at D28 and treatment related side-effect after the CAR NK cell infusion and the long-term efficacy. Results: As of data cut (February 26, 2021), 5 pts have finished CAR NK cells infusion. The median age was 43 (18-65) years-old and the median tumor burden before infusion is 31% (21%-77.5%). 4 of 5 patients have received MRD negetive CR at day 28 assessment. In dose group one, three patients have received 3 rounds of CAR NK cells (6×108, 1.2×109 and 1.8×109 cells) with the interval of 7 days after last round, and only patient 1 developed grade 1 CRS represented as fever after the infusion of 1.8×109 CAR NK cells and alleviated within 24h after symptomatic treatment. Patient 1 and patient 2 received MRD negetive CR at day 14 and 21, but patient 2 relapsed at day 43 after first round infusion. In dosage group 2, patient 4 and patient 5 both received one dose of 1.8 ×109 cells CD33 CAR NK cells after precondition, patient 5 developed grade 2 CRS presenting as lasting fever for 6 days after infusion and alleviated after 5mg Dexamethasone I.V., both patient 4 and patient 5 recieved MRD negetive CR at day 28 after infusion. At the time of this abstract being uploaded, three patients remain MRD negetive CR. Image:Summary/Conclusion: Our primary data of the phase I trial have proved the primary efficacy and safety of CD33 CAR NK cells for patients with R/R AML. The efficacy needs expanded samples and longer follow up.
S249: EX VIVO HEMATOPOIETIC STEM CELL (HSC) EXPANSION USING BONE-LINING REINVIGORATING MESENCHYMAL STROMAL CELLS (RMSCS)
Authors: S. Sood, L Klein, P. Albert, F. Pilz, N. Schmitt, D. Nowak, M. Essers
Journal: HemaSphere (2022)

Background: Bone marrow transplants (BMTs) have highlighted the Hematopoietic Stem Cell (HSC) potential to restore a new functional hematopoietic system in diseased recipients. However, a major roadblock for the clinical application and translational research on HSCs is our limited potential for ex vivo HSC expansion. Aims: To develop an approach for improved ex vivo HSC expansion using novel bone-lining reinvigorating Mesenchymal Stromal Cells (rMSC)-based culture system. Methods: Using a functional approach, we developed a robust pipeline for the fluorescence-activated cell sorting (FACS)-based isolation and ex vivo expansion of rMSCs from both murine and patient-individualized human samples. We tested the long-term HSC expansion potential in the rMSC-based co-culture system, phenotypically using FACS based proliferation analysis and functionally using limiting dilution and colony forming assays. Further, we performed transplantation experiments to study the hematopoietic reconstitution ability of the ex vivo expanded HSCs. Moreover, we expanded a single HSC over multiple cell divisions using our culture system to demonstrate bona fide HSC self-renewal potential of the rMSC-based system. Results: We propose a potent ex vivo HSC expansion system based on novel bone lining-derived reinvigorating Mesenchymal Stromal Cells (rMSCs). Both bulk- and single-HSCs expanded long-term using the rMSC co-culture system maintained phenotypic stemness over multiple cell differentiation cycles and possessed functional bone marrow reconstitution capabilities upon transplant. Notably, our rMSC co-culture system outperformed existing alternatives for HSC expansion including systems using stromal cells, non-cellular coating factors, or different medium compositions. Further, our results highlight the reliable isolation and robust culture of human rMSCs using our experimental strategy, and the potential to also utilize the rMSC co-culture system for the ex vivo expansion of human HSCs. Summary/Conclusion: We could demonstrate that our rMSC-based system for HSC expansion can play a pivotal role in research to reduce the number of mice used for ex vivo experiments. Moreover, our data also shows that the rMSC-based co-culture can be used for human HSC expansion, opening possibilities of applying this potent system for research on numerous diseases including immunodeficiencies and leukaemia.
P1067: PHASE 2 STUDY OF ORAL THALIDOMIDE-CYCLOPHOSPHAMIDE-DEXAMETHASONE FOR RECURRENT/REFRACTORY ADULT LANGERHANS CELL HISTIOCYTOSIS
Authors: J.-N. Wang, T. Liu, A.-L. Zhao, B.-J. Pan, J. Sun, J. Li, D.-B. Zhou, M.-H. Duan, X.-X. Cao
Journal: HemaSphere (2022)

Background: Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm with various clinical manifestations and heterogeneous prognoses. No standard therapy is currently available for adults with recurrent/refractory LCH. Aims: To determine the efficacy and safety of oral thalidomide combined with cyclophosphamide and dexamethasone (TCD) regimens in the treatment of recurrent/refractory LCH among adult patients. Methods: This single-center, single-arm, phase 2 study enrolled 32 recurrent/refractory LCH patients between October 2019 and August 2021. The final follow-up date was October 31st, 2021.The TCD regimen (thalidomide 100 mg daily, cyclophosphamide 300 mg/m2 Day 1, 8, 15, and dexamethasone 40 mg Day 1, 8, 15, 22 every 4 weeks) was administered for 12 cycles and then thalidomide alone as maintenance for 12 months. The primary endpoint was event-free survival (EFS). Events were defined as progression during or after TCD therapy or death from any cause. Results: The median number of prior lines of systemic treatment was 1 (range 1-4), and all patients received a cytarabine-based regimen as first-line or second-line therapy. After a median follow-up of 22 months (range 5-24 months), no patient died of all causes. The overall response rate was 87.5%, including 18 patients (56.3%) achieving complete remission and 10 patients (31.3%) as partial remission. The estimated 24-month EFS was 64.0%. Fourteen patients (43.7%) had risk organ involvement. Patients with risk organ involvement had a similar EFS compared to patients without risk organ involvement (P=0.38). The common toxicities of the TCD regimen include grade 1-2 constipation (12.5%), grade 1-2 tiredness (9.4%) and grade 2 peripheral neuropathy (12.5%). Summary/Conclusion: Oral thalidomide, cyclophosphamide and dexamethasone are effective and safe regimen for recurrent/refractory LCH patients, particularly for patients with risk organ involvement.